Separase has recently been identified as a cysteine protease that cleaves the Scc1 subunit of cohesin, a complex protein that physically connects sister chromatids and serves important functions in mitotic spindle dynamics. This proposal applies the recently described technique of peptide morphing in the rational design and synthesis of small nonpeptidic molecules to bind and inhibit separase. It is our hope that this proposal will demonstrate the power of peptide morphing by presenting a functionally rich and stereo diversified ligand structure to a protein target of urgent biologic interest and significance. Inhibition of separase, particularly at the active site, should shed light on key aspects of chromosome biology. [unreadable] [unreadable]